Gluconeogenesis

Question 1

What is gluconeogenesis?

Answer 1

• Glucose formation from precursors/ substrates such as lactate, glycerol, and amino acids

Question 2

Where does gluconeogenesis occur?

Answer 2

• Mostly in liver.
• Some in Kidneys.

Question 3

Is Gluconeogenesis the reverse of glycolysis?

Answer 3

No, as there are 3 irreversible steps in glycolysis:

1. Glucose to glucose 6-P (hexokinase)
2. Fructose 6-P (phosphofructokinase)
3. Phosphoenolpyruvate to pyruvate (pyruvate kinase)

Question 4

What are the sources of substrates needed for gluconeogenesis?

Answer 4

1. Lactate = anaerobic glycolysis via lactate dehydrogenase .
2. Glycerol = from adipose tissues during hydrolysis of TAG into blood (glycerol to glycerol phosphate via glycerol kinase. Glycerol phosphate to DHAP and then DHAP to glyceraldehyde 3-P).
3. Amino acids converted to TCA intermediates
   & to oxaloacetate (OAA) via TCA cycle. (OAA= direct precursor of phosphoenolpyruvate)

**Acetyl coA release when FA mobilised:
so ^Fatty acid breakdown = ^glycerol & ^acetyl coA

Question 4

Why is Acetyl CoA not considered a substrate for
gluconeogenesis?

Answer 4

• Acetyl-CoA is not used in gluconeogenesis because it cannot be converted to pyruvate.

Question 5

How is the irreversible action of pyruvate kinase bypassed in gluconeogenesis?

Answer 5

1. Pyruvate is converted to oxaloacetate via pyruvate carboxylase
2. Oxaloacetate is converted to phosphoenolpyruvate via PEP carboxykinase

Question 6

What is the intermediate step in converting oxaloacetate to glucose?

Answer 6

• Phosphoenolpyruvate (PEP) via PEP carboxykinase.

-This happens in mitochondrion and cytosol.

Question 7

How does oxaloacetate cross mitochondrial membrane?

Answer 7

• Converted to malate or aspartate which can cross the membrane and be reconverted in cytosol

Question 7

How is the irreversible action of phosphofructokinase (rate limiting step in glycolysis) bypassed in gluconeogenesis?

Answer 7

• Fructose 1,6 bisphosphatase converts fructose 1,6 bisphosphate to fructose 6 phosphate.

Question 8

What inhibits the action of fructose 1,6 bisphosphatase?

Answer 8

1. AMP
2. Fructose 2,6, bisphosphate: F-2,6-BP levels decreased by glucagon. Thus, glucagon increases rate of gluconeogenesis.

Question 9

How is the irreversible action of hexokinase bypassed in gluconeogenesis?

Answer 9

1. G6P is transported to ER via glucose-6-phosphate translocase
2. Glucose-6-phosphatase releases phosphate (only in liver and kidney).

Question 10

How is gluconeogenesis activated and regulated?

Answer 10

1. Gluconeogenesis is activated when energy is required (i.e., low ATP/AMP ratio) and inhibited if there is an excess of energy available.

-Activation: Glucagon

-Inhibition: Insulin